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Melanoma: HELP
Articles by Jonathan Simon Cebon
Based on 65 articles published since 2010
(Why 65 articles?)
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Between 2010 and 2020, J. S. Cebon wrote the following 65 articles about Melanoma.
 
+ Citations + Abstracts
Pages: 1 · 2 · 3
1 Review Effects of epithelial to mesenchymal transition on T cell targeting of melanoma cells. 2014

Woods, Katherine / Pasam, Anupama / Jayachandran, Aparna / Andrews, Miles C / Cebon, Jonathan. ·Cancer Immunobiology Laboratory, Ludwig Institute for Cancer Research, Melbourne-Austin Branch, Olivia Newton John Cancer and Wellness Centre , Melbourne, VIC , Australia ; School of Cancer Medicine, La Trobe University , Melbourne, VIC , Australia. ·Front Oncol · Pubmed #25566505.

ABSTRACT: Melanoma cells can switch phenotype in a manner similar to epithelial to mesenchymal transition (EMT). In this perspective article, we address the effects of such phenotype switching on T cell targeting of tumor cells. During the EMT-like switch in phenotype, a concomitant change in expression of multiple tumor antigens occurs. Melanoma cells undergoing EMT escape from killing by T cells specific for antigens whose expression is downregulated by this process. We discuss melanoma antigens whose expression is influenced by EMT. We assess the effect of changes in the expressed tumor antigen repertoire on T-cell mediated tumor recognition and killing. In addition to escape from T cell immunity via changes in antigen expression, mesenchymal-like melanoma cells are generally more resistant to classical chemotherapy and radiotherapy. However, we demonstrate that when targeting antigens whose expression is unaltered during EMT, the capacity of T cells to kill melanoma cell lines in vitro is not influenced by their phenotype. When considering immune therapies such as cancer vaccination, these data suggest escape from T cell killing due to phenotype switching in melanoma could potentially be avoided by careful selection of target antigen.

2 Review Evolving role of tumor antigens for future melanoma therapies. 2014

Andrews, Miles C / Woods, Katherine / Cebon, Jonathan / Behren, Andreas. ·Ludwig Institute for Cancer Research Ltd, Olivia Newton-John Cancer & Wellness Centre, Cancer Immunobiology, Heidelberg, VIC, Australia. ·Future Oncol · Pubmed #25052755.

ABSTRACT: Human tumor rejection antigens recognized by T lymphocytes were first defined in the early 1990s and the identification of shared tumor-restricted antigens sparked hopes for the development of a therapeutic vaccination to treat cancer, including melanoma. Despite decades of intense preclinical and clinical research, the success of anticancer vaccines based on these antigens has been limited. While melanoma is a highly immunogenic tumor, the ability to prime immunity with vaccines has not generally translated into objective disease regression. However, with the development of small molecules targeting oncogenic proteins, such as V600-mutated BRAF, and immune checkpoint inhibitors with demonstrable long-lasting clinical benefit, new opportunities for antigen-targeted directed therapies are emerging.

3 Review Immune consequences of kinase inhibitors in development, undergoing clinical trials and in current use in melanoma treatment. 2014

Vella, Laura J / Andrews, Miles C / Behren, Andreas / Cebon, Jonathan / Woods, Katherine. ·Ludwig Institute for Cancer Research, Melbourne-Austin Branch, Cancer Immuno-biology Laboratory, Heidelberg, VIC 3084, Australia. ·Expert Rev Clin Immunol · Pubmed #24939732.

ABSTRACT: Metastatic malignant melanoma is a frequently fatal cancer. In recent years substantial therapeutic progress has occurred with the development of targeted kinase inhibitors and immunotherapeutics. Targeted therapies often result in rapid clinical benefit however responses are seldom durable. Immune therapies can result in durable disease control but responses may not be immediate. Optimal cancer therapy requires both rapid and durable cancer control and this can likely best be achieved by combining targeted therapies with immunotherapeutics. To achieve this, a detailed understanding of the immune consequences of the various kinase inhibitors, in development, clinical trial and currently used to treat melanoma is required.

4 Review Melanoma vaccines: developments over the past 10 years. 2011

Klein, Oliver / Schmidt, Christopher / Knights, Ashley / Davis, Ian D / Chen, Weisan / Cebon, Jonathan. ·Ludwig Institute for Cancer Research, Austin Branch, Austin Hospital, Studley Road, Heidelberg, Victoria, 3084, Australia. ·Expert Rev Vaccines · Pubmed #21692705.

ABSTRACT: Decades of preclinical evaluation and clinical trials into melanoma vaccines have yielded spectacular progress in our understanding of melanoma antigens and the immune mechanisms of tumor rejection. Key insights and the results of their clinical evaluation are reviewed in this article. Unfortunately, durable clinical benefit following vaccination remains uncommon. Two recent clinical advances that will impact on melanoma vaccine development are trials with inhibitors of CTLA-4 and oncogenic BRAF. Long-term therapeutic control of melanoma will require integration of specific active immunotherapy with these emerging successful therapies from the disparate fields of immune regulation and signal transduction.

5 Clinical Trial Autoantibodies May Predict Immune-Related Toxicity: Results from a Phase I Study of Intralesional 2018

Da Gama Duarte, Jessica / Parakh, Sagun / Andrews, Miles C / Woods, Katherine / Pasam, Anupama / Tutuka, Candani / Ostrouska, Simone / Blackburn, Jonathan M / Behren, Andreas / Cebon, Jonathan. ·Olivia Newton-John Cancer Research Institute, Heidelberg, VIC, Australia. · School of Cancer Medicine, La Trobe University, Heidelberg, VIC, Australia. · Ludwig Institute for Cancer Research, Melbourne-Austin Branch, Melbourne, VIC, Australia. · MD Anderson Cancer Center, University of Texas, Houston, TX, United States. · Department of Integrative Biomedical Sciences and Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa. · Sengenics Corporation, Singapore, Singapore. ·Front Immunol · Pubmed #29552014.

ABSTRACT: Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of advanced melanoma. The first ICI to demonstrate clinical benefit, ipilimumab, targets cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4); however, the long-term overall survival is just 22%. More than 40 years ago intralesional (IL)

6 Clinical Trial Long-Term Outcomes in Patients With BRAF V600-Mutant Metastatic Melanoma Who Received Dabrafenib Combined With Trametinib. 2018

Long, Georgina V / Eroglu, Zeynep / Infante, Jeffrey / Patel, Sapna / Daud, Adil / Johnson, Douglas B / Gonzalez, Rene / Kefford, Richard / Hamid, Omid / Schuchter, Lynn / Cebon, Jonathan / Sharfman, William / McWilliams, Robert / Sznol, Mario / Redhu, Suman / Gasal, Eduard / Mookerjee, Bijoyesh / Weber, Jeffrey / Flaherty, Keith T. ·Georgina V. Long, University of Sydney, and Royal North Shore Hospital · Richard Kefford, Macquarie University, Sydney, and Westmead Hospital, Westmead, New South Wales · Jonathan Cebon, Ludwig Institute for Cancer Research, Melbourne, Victoria, Australia · Zeynep Eroglu, Moffitt Cancer Center, Tampa, FL · Jeffrey Infante, Tennessee Oncology · Douglas B. Johnson, Vanderbilt-Ingram Cancer Center, Nashville, TN · Sapna Patel, The University of Texas MD Anderson Cancer Center, Houston, TX · Adil Daud, University of California, San Francisco, San Francisco · Omid Hamid, The Angeles Clinic and Research Institute, Los Angeles, CA · Rene Gonzalez, University of Colorado, Denver, CO · Lynn Schuchter, University of Pennsylvania, Philadelphia, PA · William Sharfman, Sidney Kimmel Cancer Center, Baltimore, MD · Robert McWilliams, Mayo Clinic, Rochester, MN · Mario Sznol, Yale University, New Haven, CT · Suman Redhu, Eduard Gasal, and Bijoyesh Mookerjee, Novartis, East Hanover, NJ · Jeffrey Weber, New York University Langone Medical Center, New York, NY · and Keith T. Flaherty, Dana-Farber/Harvard Cancer Center, Boston, MA. ·J Clin Oncol · Pubmed #28991513.

ABSTRACT: Purpose To report 5-year landmark analysis efficacy and safety outcomes in patients with BRAF V600-mutant metastatic melanoma (MM) who received BRAF inhibitor dabrafenib (D) and MEK inhibitor trametinib (T) combination therapy versus D monotherapy in the randomized phase II BRF113220 study part C. Patients and Methods BRAF inhibitor-naive patients with BRAF V600-mutant MM were randomly assigned 1:1:1 to receive D 150 mg twice a day, D 150 mg twice a day plus T 1 mg once daily, or D 150 mg twice a day plus T 2 mg once daily (D + T 150/2). Patients who received D monotherapy could cross over to D + T 150/2 postprogression. Efficacy and safety were analyzed 4 and 5 years after initiation in patients with ≥ 5 years of follow-up. Results As of October 13, 2016, 18 patients who received D + T 150/2 remained in the study (13 [24%] of 54 enrolled at this dose plus five [11%] of 45 initially administered D who crossed over to D + T). With D + T 150/2, overall survival (OS; 4 years, 30%; 5 years, 28%) and progression-free survival (4 and 5 years, both 13%) appeared to stabilize with extended follow-up. Increased OS was observed in patients who received D + T with baseline normal lactate dehydrogenase (5 years, 45%) and normal lactate dehydrogenase with fewer than three organ sites with metastasis (5 years, 51%). With extended follow-up, one additional patient who received D + T 150/2 improved from a partial to a complete response. No new safety signals were observed. Conclusion This 5-year analysis represents the longest follow-up to date with BRAF + MEK inhibitor combination therapy in BRAF V600-mutant MM. Consistent with trends observed in landmark analyses with shorter follow-up, this therapy elicits durable plateaus of long-term OS and progression-free survival that last ≥ 5 years in some patients with MM.

7 Clinical Trial Patient-reported outcomes in KEYNOTE-006, a randomised study of pembrolizumab versus ipilimumab in patients with advanced melanoma. 2017

Petrella, Teresa M / Robert, Caroline / Richtig, Erika / Miller, Wilson H / Masucci, Giuseppe V / Walpole, Euan / Lebbe, Celeste / Steven, Neil / Middleton, Mark R / Hille, Darcy / Zhou, Wei / Ibrahim, Nageatte / Cebon, Jonathan. ·Sunnybrook Health Sciences Centre, University of Toronto, 2075 Bayview Ave, T2-041, Toronto, ON, M4N 3M5, Canada. Electronic address: teresa.petrella@sunnybrook.ca. · Gustave Roussy and Université Paris-Sud, 114 Rue Edouard Vaillant, 94800 Villejuif, France. Electronic address: caroline.robert@gustaveroussy.fr. · Medical University of Graz, Auenbruggerpl. 2, 8036 Graz, Graz, Austria. Electronic address: erika.richtig@medunigraz.at. · Segal Cancer Centre, Jewish General Hospital, Rossy Cancer Network, and McGill University, 3755 Ch de la Côte-Sainte-Catherine, Montreal, QC, H3T 1E2, Canada. Electronic address: wilsonmiller@gmail.com. · Karolinska Institute, Solnavägen 1, 171 77 Solna, Stockholm, Sweden. Electronic address: giuseppe.masucci@ki.se. · Princess Alexandra Hospital and The University of Queensland, 199 Ipswich Rd, Woolloongabba, Brisbane, QLD 4102, Australia. Electronic address: euan.walpole@health.qld.gov.au. · APHP, Dermatology and CIC, Université Paris Diderot, Hôpital Saint-Louis, 1 Avenue Claude Vellefaux, 75010 Paris, France. Electronic address: celeste.lebbe@aphp.fr. · Queen Elizabeth Hospital Birmingham, Mindelsohn Way, Birmingham B15 2TH, UK. Electronic address: N.M.Steven@bham.ac.uk. · The Churchill Hospital and The University of Oxford, Old Rd, Headington, Oxford OX3 7LE, UK. Electronic address: mark.middleton@oncology.ox.ac.uk. · Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA. Electronic address: darcy_hille@merck.com. · Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA. Electronic address: wei.zhou2@merck.com. · Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA. Electronic address: nageatte.ibrahim@merck.com. · Olivia Newton-John Cancer Research Institute, Austin Health, School of Cancer Medicine, La Trobe University, 145 Studley Road, Heidelberg VIC 3084, Melbourne, Australia. Electronic address: jonathan.cebon@onjcri.org.au. ·Eur J Cancer · Pubmed #28987768.

ABSTRACT: OBJECTIVE: Report results of patient-reported health-related quality of life (HRQoL) and symptoms from phase III KEYNOTE-006 study of pembrolizumab versus ipilimumab in patients with ipilimumab-naive advanced melanoma. PATIENTS AND METHODS: Patients received pembrolizumab 10 mg/kg every 2 (Q2W) or every 3 weeks (Q3W) for up to 2 years, or four cycles of ipilimumab 3 mg/kg Q3W. The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30) was administered at baseline and throughout the study. Patient-reported outcome (PRO) analyses were pre-specified exploratory endpoints; the primary PRO assessment was the score change from baseline to week 12 in EORTC QLQ-C30 global health status (GHS)/HRQoL score between the arms using constrained longitudinal data analysis. RESULTS: The PRO analysis population included 776 patients: pembrolizumab Q2W (n = 270); pembrolizumab Q3W (n = 266); ipilimumab (n = 240). Baseline GHS was similar across arms. QLQ-C30 compliance rates at week 12 were 87% (n = 214), 97% (n = 226), and 96% (n = 178), for the pembrolizumab Q2W, pembrolizumab Q3W, and ipilimumab arms, respectively. From baseline to week 12, GHS/HRQoL scores were better maintained with pembrolizumab than with ipilimumab (decrease of -1.9 and -2.5 for pembrolizumab versus -10.0 for ipilimumab; p < 0.001 for each pembrolizumab arm versus ipilimumab). Fewer patients treated with pembrolizumab experienced deterioration in GHS at week 12 (31% for pembrolizumab Q2W; 29% for Q3W and 44% for ipilimumab), with similar trends observed for individual functioning and symptoms scales. CONCLUSIONS: HRQoL was better maintained with pembrolizumab than with ipilimumab in patients with ipilimumab-naive advanced melanoma. CLINICALTRIALS. GOV IDENTIFIER: NCT01866319.

8 Clinical Trial Overall Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma. 2017

Wolchok, Jedd D / Chiarion-Sileni, Vanna / Gonzalez, Rene / Rutkowski, Piotr / Grob, Jean-Jacques / Cowey, C Lance / Lao, Christopher D / Wagstaff, John / Schadendorf, Dirk / Ferrucci, Pier F / Smylie, Michael / Dummer, Reinhard / Hill, Andrew / Hogg, David / Haanen, John / Carlino, Matteo S / Bechter, Oliver / Maio, Michele / Marquez-Rodas, Ivan / Guidoboni, Massimo / McArthur, Grant / Lebbé, Celeste / Ascierto, Paolo A / Long, Georgina V / Cebon, Jonathan / Sosman, Jeffrey / Postow, Michael A / Callahan, Margaret K / Walker, Dana / Rollin, Linda / Bhore, Rafia / Hodi, F Stephen / Larkin, James. ·From the Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York (J.D.W., M.A.P., M.K.C.) · Oncology Institute of Veneto Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Padua (V.C.-S.), European Institute of Oncology, Milan (P.F.F.), Center for Immuno-Oncology, University Hospital of Siena, Istituto Toscano Tumori, Siena (M.M.), the Immunotherapy and Somatic Cell Therapy Unit, IRCCS Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori, Meldola (M.G.), and Istituto Nazionale Tumori Fondazione Pascale, Naples (P.A.A.) - all in Italy · University of Colorado, Denver (R.G.) · Maria Sklodowska-Curie Institute-Oncology Center, Warsaw, Poland (P.R.) · Aix-Marseille University, Hôpital de la Timone, Marseille (J.-J.G.), and Assistance Publique-Hôpitaux de Paris, Dermatology and Centres d'Investigation Clinique, INSERM Unité 976, Hôpital Saint-Louis, Université Paris Diderot, Paris (C.L.) - both in France · Texas Oncology-Baylor Cancer Center, Dallas (C.L.C.) · University of Michigan, Ann Arbor (C.D.L.) · the College of Medicine, Swansea University, Swansea (J.W.), and Royal Marsden NHS Foundation Trust, London (J.L.) - both in the United Kingdom · the Department of Dermatology, University of Essen, Essen, and the German Cancer Consortium, Heidelberg - both in Germany (D.S.) · Cross Cancer Institute, Edmonton, AB (M.S.), and Princess Margaret Cancer Centre, Toronto (D.H.) - both in Canada · Universitäts Spital, Zurich, Switzerland (R.D.) · Tasman Oncology Research, Southport Gold Coast, QLD (A.H.), Crown Princess Mary Cancer Centre, Melanoma Institute Australia, University of Sydney (M.S.C.), and Melanoma Institute Australia, University of Sydney, and Royal North Shore and Mater Hospitals (G.V.L.), Sydney, and Peter MacCallum Cancer Centre (G.M.) and the Olivia Newton-John Cancer Research Institute, University of Melbourne (J.C.), Melbourne, VIC - all in Australia · Netherlands Cancer Institute, Amsterdam (J.H.) · University Hospitals Leuven, KU Leuven, Leuven, Belgium (O.B.) · General University Hospital Gregorio Marañón, Madrid (I.M.-R.) · Northwestern University, Chicago (J.S.) · Bristol-Myers Squibb, Princeton, NJ (D.W., L.R., R.B.) · and the Dana-Farber Cancer Institute, Boston (F.S.H.). ·N Engl J Med · Pubmed #28889792.

ABSTRACT: BACKGROUND: Nivolumab combined with ipilimumab resulted in longer progression-free survival and a higher objective response rate than ipilimumab alone in a phase 3 trial involving patients with advanced melanoma. We now report 3-year overall survival outcomes in this trial. METHODS: We randomly assigned, in a 1:1:1 ratio, patients with previously untreated advanced melanoma to receive nivolumab at a dose of 1 mg per kilogram of body weight plus ipilimumab at a dose of 3 mg per kilogram every 3 weeks for four doses, followed by nivolumab at a dose of 3 mg per kilogram every 2 weeks; nivolumab at a dose of 3 mg per kilogram every 2 weeks plus placebo; or ipilimumab at a dose of 3 mg per kilogram every 3 weeks for four doses plus placebo, until progression, the occurrence of unacceptable toxic effects, or withdrawal of consent. Randomization was stratified according to programmed death ligand 1 (PD-L1) status, BRAF mutation status, and metastasis stage. The two primary end points were progression-free survival and overall survival in the nivolumab-plus-ipilimumab group and in the nivolumab group versus the ipilimumab group. RESULTS: At a minimum follow-up of 36 months, the median overall survival had not been reached in the nivolumab-plus-ipilimumab group and was 37.6 months in the nivolumab group, as compared with 19.9 months in the ipilimumab group (hazard ratio for death with nivolumab plus ipilimumab vs. ipilimumab, 0.55 [P<0.001]; hazard ratio for death with nivolumab vs. ipilimumab, 0.65 [P<0.001]). The overall survival rate at 3 years was 58% in the nivolumab-plus-ipilimumab group and 52% in the nivolumab group, as compared with 34% in the ipilimumab group. The safety profile was unchanged from the initial report. Treatment-related adverse events of grade 3 or 4 occurred in 59% of the patients in the nivolumab-plus-ipilimumab group, in 21% of those in the nivolumab group, and in 28% of those in the ipilimumab group. CONCLUSIONS: Among patients with advanced melanoma, significantly longer overall survival occurred with combination therapy with nivolumab plus ipilimumab or with nivolumab alone than with ipilimumab alone. (Funded by Bristol-Myers Squibb and others; CheckMate 067 ClinicalTrials.gov number, NCT01844505 .).

9 Clinical Trial Oncolytic Virotherapy Promotes Intratumoral T Cell Infiltration and Improves Anti-PD-1 Immunotherapy. 2017

Ribas, Antoni / Dummer, Reinhard / Puzanov, Igor / VanderWalde, Ari / Andtbacka, Robert H I / Michielin, Olivier / Olszanski, Anthony J / Malvehy, Josep / Cebon, Jonathan / Fernandez, Eugenio / Kirkwood, John M / Gajewski, Thomas F / Chen, Lisa / Gorski, Kevin S / Anderson, Abraham A / Diede, Scott J / Lassman, Michael E / Gansert, Jennifer / Hodi, F Stephen / Long, Georgina V. ·University of California at Los Angeles, Jonsson Comprehensive Cancer Center, Los Angeles, CA, USA. Electronic address: aribas@mednet.ucla.edu. · University Hospital of Zurich, Zurich, Switzerland. · Roswell Park Cancer Institute, Buffalo, NY, USA. · The West Clinic, Memphis, TN, USA. · University of Utah Huntsman Cancer Institute, Salt Lake City, UT, USA. · Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland. · Fox Chase Cancer Center, Philadelphia, PA, USA. · Hospital Clinic i Provincial de Barcelona, Barcelona, Spain. · Olivia Newton-John Cancer Research Institute, Austin Health, School of Cancer Medicine, LaTrobe University, Heidelberg, VIC, Australia. · Hopitaux Universitaires de Genève, Geneva, Switzerland. · University of Pittsburgh Cancer Institute and Hillman UPMC Cancer Center, Pittsburgh, PA, USA. · The University of Chicago School of Medicine, Chicago, IL, USA. · Amgen Inc., Thousand Oaks, CA, USA. · Amgen Inc., South San Francisco, CA, USA. · Merck & Co., Inc., Kenilworth, NJ, USA. · Dana-Farber Cancer Institute, Boston, MA, USA. · Melanoma Institute Australia, The University of Sydney and Royal North Shore and Mater Hospitals, Sydney, NSW, Australia. ·Cell · Pubmed #28886381.

ABSTRACT: Here we report a phase 1b clinical trial testing the impact of oncolytic virotherapy with talimogene laherparepvec on cytotoxic T cell infiltration and therapeutic efficacy of the anti-PD-1 antibody pembrolizumab. Twenty-one patients with advanced melanoma were treated with talimogene laherparepvec followed by combination therapy with pembrolizumab. Therapy was generally well tolerated, with fatigue, fevers, and chills as the most common adverse events. No dose-limiting toxicities occurred. Confirmed objective response rate was 62%, with a complete response rate of 33% per immune-related response criteria. Patients who responded to combination therapy had increased CD8

10 Clinical Trial Standard-dose pembrolizumab in combination with reduced-dose ipilimumab for patients with advanced melanoma (KEYNOTE-029): an open-label, phase 1b trial. 2017

Long, Georgina V / Atkinson, Victoria / Cebon, Jonathan S / Jameson, Michael B / Fitzharris, Bernie M / McNeil, Catriona M / Hill, Andrew G / Ribas, Antoni / Atkins, Michael B / Thompson, John A / Hwu, Wen-Jen / Hodi, F Stephen / Menzies, Alexander M / Guminski, Alexander D / Kefford, Richard / Kong, Benjamin Y / Tamjid, Babak / Srivastava, Archana / Lomax, Anna J / Islam, Mohammed / Shu, Xinxin / Ebbinghaus, Scot / Ibrahim, Nageatte / Carlino, Matteo S. ·Melanoma Institute Australia, University of Sydney, Mater Hospital, Sydney, NSW, Australia; Royal North Shore Hospital, Sydney, NSW, Australia. Electronic address: georgina.long@sydney.edu.au. · Gallipoli Medical Research Foundation, Greenslopes Private Hospital, Greenslopes, QLD, Australia; University of Queensland, Brisbane, QLD, Australia. · Olivia Newton-John Cancer Research Institute, Austin Health, School of Cancer Medicine, LaTrobe University, Heidelberg, VIC, Australia. · Regional Cancer Centre, Waikato Hospital, Hamilton, New Zealand. · Canterbury District Health Board, Christchurch Hospital, Christchurch, New Zealand. · Royal Prince Alfred Hospital, Melanoma Institute Australia, University of Sydney, Sydney, NSW, Australia; Chris O'Brien Lifehouse, Camperdown, NSW, Australia. · Tasman Oncology Research, Southport Gold Coast, QLD, Australia. · Department of Medicine, University of California, Los Angeles, Los Angeles, CA, USA. · Georgetown-Lombardi Comprehensive Cancer Center, Washington, DC, USA. · Department of Medicine, University of Washington, Seattle, WA, USA. · University of Texas MD Anderson Cancer Center, Houston, TX, USA. · Dana-Farber Cancer Institute, Boston, MA, USA. · Melanoma Institute Australia, University of Sydney, Mater Hospital, Sydney, NSW, Australia; Royal North Shore Hospital, Sydney, NSW, Australia. · Westmead Hospital, Melanoma Institute Australia, Macquarie University, Sydney, NSW, Australia. · Westmead Hospital, Westmead, NSW, Australia; Melanoma Institute Australia, University of Sydney, Sydney, NSW, Australia; Blacktown Hospital, Blacktown, NSW, Australia. · Merck & Co, Kenilworth, NJ, USA. ·Lancet Oncol · Pubmed #28729151.

ABSTRACT: BACKGROUND: Reduced-dose nivolumab in combination with standard-dose ipilimumab improves objective response and progression-free survival compared with standard-dose ipilimumab alone, but increases toxicity. We assessed the safety and anti-tumour activity of standard-dose pembrolizumab in combination with reduced-dose ipilimumab. METHODS: In this open-label, phase 1b trial, we recruited patients from 12 medical centres in Australia, New Zealand, and the USA. Eligible patients were aged at least 18 years, had advanced melanoma, had an Eastern Coooperative Oncology Group performance status of 0 or 1, had measurable disease according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, had adequate organ function, had resolution of toxic effects of the most recent previous chemotherapy to grade 1 or less, had no active autoimmune disease requiring systemic steroids or immunosuppressive agents, had no active non-infectious pneumonitis, had no uncontrolled thyroid dysfunction or diabetes, had no active brain metastases, and had not received previous immune checkpoint inhibitor therapy. Patients received intravenous pembrolizumab 2 mg/kg plus intravenous ipilimumab 1 mg/kg every 3 weeks for four doses, followed by intravenous pembrolizumab 2 mg/kg every 3 weeks for up to 2 years or disease progression, intolerable toxicity, withdrawal of consent, or investigator decision. The primary endpoint was safety and tolerability. The proportion of patients achieving an objective response assessed per RECIST version 1.1 by independent central review and overall survival were secondary endpoints. We also assessed progression-free survival. The primary endpoint was assessed in all patients who received at least one dose of combination therapy. Activity was assessed in all enrolled patients. This trial is registered with ClinicalTrials.gov, number NCT02089685. Enrolment into this cohort is closed, but patients are still being monitored for safety and anti-tumour activity. FINDINGS: Between Jan 13, 2015, and Sept 17, 2015, we enrolled and treated 153 patients. As of the Oct 17, 2016, cutoff date, median follow-up was 17·0 months (IQR 14·8-18·8). 110 (72%) of 153 patients received all four pembrolizumab plus ipilimumab doses; 64 (42%) remained on pembrolizumab monotherapy. 110 grade 3-4 treatment-related adverse events occurred in 69 (45%) patients. No treatment-related deaths occurred. Treatment-related adverse events led to discontinuation of pembrolizumab and ipilimumab in 22 (14%) patients, including 17 (11%) who discontinued both treatments for the same event and five (3%) who discontinued ipilimumab for one event and later discontinued pembrolizumab for another. 12 (8%) patients discontinued ipilimumab only and 14 (9%) discontinued pembrolizumab only because of treatment-related adverse events. 158 immune-mediated adverse events of any grade occurred in 92 (60%) patients, and 50 immune-mediated adverse events of grade 3-4 occurred in 42 (27%) patients; the most common immune-mediated adverse events were hypothyroidism (25 [16%]) and hyperthyroidism (17 [11%]). 93 (61% [95% CI 53-69]) patients achieved an objective response. Estimated 1 year progression-free survival was 69% (95% CI 60-75), and estimated 1 year overall survival was 89% (95% CI 83-93). INTERPRETATION: Standard-dose pembrolizumab given in combination with four doses of reduced-dose ipilimumab followed by standard-dose pembrolizumab has a manageable toxicity profile and provides robust anti-tumour activity in patients with advanced melanoma. These data suggest that standard-dose pembrolizumab plus reduced-dose ipilimumab might be a tolerable, efficacious treatment option for patients with advanced melanoma. A randomised phase 2 trial of alternative dosing strategies of this combination is underway. FUNDING: Merck & Co, Inc.

11 Clinical Trial Overall Survival and Durable Responses in Patients With BRAF V600-Mutant Metastatic Melanoma Receiving Dabrafenib Combined With Trametinib. 2016

Long, Georgina V / Weber, Jeffrey S / Infante, Jeffrey R / Kim, Kevin B / Daud, Adil / Gonzalez, Rene / Sosman, Jeffrey A / Hamid, Omid / Schuchter, Lynn / Cebon, Jonathan / Kefford, Richard F / Lawrence, Donald / Kudchadkar, Ragini / Burris, Howard A / Falchook, Gerald S / Algazi, Alain / Lewis, Karl / Puzanov, Igor / Ibrahim, Nageatte / Sun, Peng / Cunningham, Elizabeth / Kline, Amy S / Del Buono, Heather / McDowell, Diane Opatt / Patel, Kiran / Flaherty, Keith T. ·Georgina V. Long, Melanoma Institute Australia · The University of Sydney · Richard F. Kefford, Melanoma Institute Australia · The University of Sydney · Macquarie University, Sydney · Westmead Hospital, Westmead · Jonathan Cebon, Austin Health, Melbourne, Victoria, Australia · Jeffrey S. Weber and Ragini Kudchadkar, Moffitt Cancer Center, Tampa, FL · Jeffrey R. Infante and Howard A. Burris III, Sarah Cannon Research Institute/Tennessee Oncology · Kevin B. Kim, California Pacific Medical Center · Adil Daud, Alain Algazi, University of California, San Francisco, San Francisco · Omid Hamid, The Angeles Clinic and Research Institute, Los Angeles, CA · Rene Gonzalez, Karl Lewis, University of Colorado · Gerald S. Falchook, Sarah Cannon Research Institute at HealthONE, Denver, CO · Jeffrey A. Sosman, Igor Puzanov, Vanderbilt University Medical Center, Nashville, TN · Lynn Schuchter, University of Pennsylvania Abramson Cancer Center · Nageatte Ibrahim, Elizabeth Cunningham, Merck · Peng Sun, Amy S. Kline, Heather Del Buono, Diane Opatt McDowell, GlaxoSmithKline, Philadelphia, PA · Donald Lawrence and Kiran Patel, Incyte Corporation, Wilmington, DE · and Keith T. Flaherty, Massachusetts General Hospital Cancer Center, Boston, MA. ·J Clin Oncol · Pubmed #26811525.

ABSTRACT: PURPOSE: To report the overall survival (OS) and clinical characteristics of BRAF inhibitor-naive long-term responders and survivors treated with dabrafenib plus trametinib in a phase I and II study of patients with BRAF V600 mutation-positive metastatic melanoma. METHODS: BRAF inhibitor-naive patients treated with dabrafenib 150 mg twice daily plus trametinib 2 mg daily (the 150/2 group) from the non-randomly assigned (part B) and randomly assigned (part C) cohorts of the study were analyzed for progression-free and OS separately. Baseline characteristics and factors on treatment were analyzed for associations with durable responses and OS. RESULTS: For BRAF inhibitor-naive patients in the 150/2 groups (n = 78), the progression-free survival at 1, 2, and 3 years was 44%, 22%, and 18%, respectively, for part B (n = 24) and 41%, 25%, and 21%, respectively, for part C (n = 54). Median OS was 27.4 months in part B and 25 months in part C. OS at 1, 2, and 3 years was 72%, 60%, and 47%, respectively, for part B and 80%, 51%, and 38%, respectively, for part C. Prolonged survival was associated with metastases in fewer than three organ sites and lower baseline lactate dehydrogenase. OS at 3 years was 62% in patients with normal baseline lactate dehydrogenase and 63% in patients with a complete response. CONCLUSION: Dabrafenib plus trametinib results in a median OS of more than 2 years in BRAF inhibitor-naive patients with BRAF V600 mutation-positive metastatic melanoma, and approximately 20% were progression free at 3 years. Durable responses occurred in patients with good prognostic features at baseline, which may be predictive.

12 Clinical Trial First-in-Man Dose-Escalation Study of the Selective BRAF Inhibitor RG7256 in Patients with BRAF V600-Mutated Advanced Solid Tumors. 2016

Dienstmann, Rodrigo / Lassen, Ulrik / Cebon, Jonathan / Desai, Jayesh / Brown, Michael P / Evers, Stefan / Su, Fei / Zhang, Weijiang / Boisserie, Frederic / Lestini, Brian / Schostack, Kathleen / Meresse, Valerie / Tabernero, Josep. ·Vall d'Hebron University Hospital, Medical Oncology, Barcelona, Spain. rdienstmann@vhio.net. · , P. Vall d'Hebron 119-129, 08035, Barcelona, Spain. rdienstmann@vhio.net. · Department of Oncology, Rigshospitalet, Copenhagen, Denmark. · Austin Hospital, Oncology Unit, Heidelberg, Australia. · Royal Melbourne Hospital, Parkville, Australia. · Cancer Clinical Trials Unit, Royal Adelaide Hospital, Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, Australia. · Pharma Research & Early Development, Roche Innovation Center Zurich, Schlieren, Switzerland. · Pharma Research & Early Development, Roche Innovation Center New York, New York, NY, USA. · Oncology Correlative Science Lead, Novartis Pharmaceutical Corporation, East Hanover, NJ, USA. · Oncology Global Clinical Research, Bristol-Myers Squibb, New York, NY, USA. · Global Development, Oncology, Bayer HealthCare Pharmaceuticals, Inc, Whippany, NJ, USA. · Pharma Research & Early Development, Roche Innovation Center Basel, Basel, Switzerland. · Vall d'Hebron University Hospital, Medical Oncology, Barcelona, Spain. jtabernero@vhio.net. · , P. Vall d'Hebron 119-129, 08035, Barcelona, Spain. jtabernero@vhio.net. ·Target Oncol · Pubmed #26310975.

ABSTRACT: BACKGROUND: BRAF mutations are a validated target for cancer therapy. A second-generation BRAF inhibitor with an improved preclinical safety profile (RG7256) was evaluated in a first-in-man study in order to determine the safety, efficacy, pharmacokinetics and pharmacodynamics in patients with BRAF V600-mutated advanced solid tumors. PATIENTS AND METHODS: Patients received RG7256 orally over 8 dose levels from 200 mg once a day (QD) to 2400 mg twice a day (BID) (50-, 100- and 150-mg tablets) using a classic 3 + 3 dose escalation design. RESULTS: In total, 45 patients were enrolled; most (87 %) had advanced melanoma (94 % BRAF V600E). RG7256 was rapidly absorbed, with limited accumulation and dose-proportional increase in exposure up to 1950 mg BID. The maximal tolerated dose (MTD) was not reached. The most common drug-related adverse events (AEs) were dyspepsia (20 %), dry skin (18 %), rash (18 %), fatigue (16 %) and nausea (13 %), mainly grade 1. Three patients (7 %) developed cutaneous squamous cell carcinoma. Photosensitivity, arthralgia and increased liver enzyme levels were each observed in only one patient each. Of 44 evaluable patients, 14 (32 %) had a partial response (melanoma and thyroid cancer). At high dose levels (>1200 mg BID), 10 of 16 (63 %) patients had a partial response. A decrease in maximum standardized uptake value (SUVmax) on FDG-PET of ≥25 % was observed in 19 of 37 patients. On-treatment reductions in pERK were documented in eight of ten paired tumor samples. CONCLUSIONS: RG7256 has a favorable safety profile compared to other BRAF inhibitors while maintaining clinical activity, and MTD was not reached. The excessive pill burden needed to provide the desired exposure, and thus concerns about patient compliance, limited further development of this agent. Study Identifier: ClinicalTrials.gov (NCT01143753).

13 Clinical Trial Low-dose cyclophosphamide enhances antigen-specific CD4(+) T cell responses to NY-ESO-1/ISCOMATRIX™ vaccine in patients with advanced melanoma. 2015

Klein, Oliver / Davis, Ian D / McArthur, Grant A / Chen, Li / Haydon, Andrew / Parente, Phillip / Dimopoulos, Nektaria / Jackson, Heather / Xiao, Kun / Maraskovsky, Eugene / Hopkins, Wendie / Stan, Rodica / Chen, Weisan / Cebon, Jonathan. ·Ludwig Institute for Cancer Research (Melbourne-Austin Branch), 147-163 Studley Road, Heidelberg, VIC, 3084, Australia, oliver.klein@ludwig.edu.au. ·Cancer Immunol Immunother · Pubmed #25662405.

ABSTRACT: Clinical outcomes from cancer vaccine trials in patients with advanced melanoma have so far been disappointing. This appears at least partially due to a state of immunosuppression in these patients induced by an expansion of regulatory cell populations including regulatory T cells (Tregs). We have previously demonstrated potent immunogenicity of the NY-ESO-1/ISCOMATRIX™ vaccine in patients with resected melanoma (study LUD99-08); however, the same vaccine induced only a few vaccine antigen-specific immune responses in patients with advanced disease (study LUD2002-013). Pre-clinical models suggest that the alkylating agent cyclophosphamide can enhance immune responses by depleting Tregs. Therefore, we have enrolled a second cohort of patients with advanced melanoma in the clinical trial LUD2002-013 to investigate whether pre-treatment with cyclophosphamide could improve the immunogenicity of the NY-ESO-1/ISCOMATRIX™ vaccine. The combination treatment led to a significant increase in vaccine-induced NY-ESO-1-specific CD4(+) T cell responses compared with the first trial cohort treated with vaccine alone. We could not detect a significant decline in regulatory T cells in peripheral blood of patients 14 days after cyclophosphamide administration, although a decline at an earlier time point cannot be excluded. Our observations support the inclusion of cyclophosphamide in combination trials with vaccines and other immune-modulatory agents.

14 Clinical Trial Combined BRAF (Dabrafenib) and MEK inhibition (Trametinib) in patients with BRAFV600-mutant melanoma experiencing progression with single-agent BRAF inhibitor. 2014

Johnson, Douglas B / Flaherty, Keith T / Weber, Jeffrey S / Infante, Jeffrey R / Kim, Kevin B / Kefford, Richard F / Hamid, Omid / Schuchter, Lynn / Cebon, Jonathan / Sharfman, William H / McWilliams, Robert R / Sznol, Mario / Lawrence, Donald P / Gibney, Geoffrey T / Burris, Howard A / Falchook, Gerald S / Algazi, Alain / Lewis, Karl / Long, Georgina V / Patel, Kiran / Ibrahim, Nageatte / Sun, Peng / Little, Shonda / Cunningham, Elizabeth / Sosman, Jeffrey A / Daud, Adil / Gonzalez, Rene. ·Douglas B. Johnson and Jeffrey A. Sosman, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center · Jeffrey R. Infante and Howard A. Burris III, Sarah Cannon Research Institute and Tennessee Oncology, Nashville, TN · Keith T. Flaherty and Donald P. Lawrence, Massachusetts General Hospital Cancer Center, Boston MA · Jeffrey S. Weber and Geoffrey T. Gibney, Moffitt Cancer Center, Tampa, FL · Kevin B. Kim and Gerald S. Falchook, University of Texas MD Anderson Cancer Center, Houston, TX · Richard F. Kefford and Georgina V. Long, Melanoma Institute Australia, University of Sydney and Westmead Hospital, Sydney, New South Wales · Jonathan Cebon, Joint Ludwig-Austin Oncology Unit, Austin Health, Melbourne, Victoria, Australia · Omid Hamid, Angeles Clinic and Research Institute, Los Angeles · Alain Algazi and Adil Daud, University of California, San Francisco, San Francisco, CA · Lynn Schuchter, University of Pennsylvania Abramson Cancer Center · Nageatte Ibrahim, Peng Sun, Shonda Little, and Elizabeth Cunningham, GlaxoSmithKline, Philadelphia, PA · William H. Sharfman, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins, Baltimore, MD · Robert R. McWilliams, Mayo Clinic, Rochester, MN · Mario Sznol, Yale University School of Medicine and Smilow Cancer Center, Yale-New Haven Hospital, New Haven, CT · Karl Lewis and Rene Gonzalez, University of Colorado, Denver, CO · and Kiran Patel, Incyte, Wilmington, DE. ·J Clin Oncol · Pubmed #25287827.

ABSTRACT: PURPOSE: Preclinical and early clinical studies have demonstrated that initial therapy with combined BRAF and MEK inhibition is more effective in BRAF(V600)-mutant melanoma than single-agent BRAF inhibitors. This study assessed the safety and efficacy of dabrafenib and trametinib in patients who had received prior BRAF inhibitor treatment. PATIENTS AND METHODS: In this open-label phase I/II study, we evaluated the pharmacology, safety, and efficacy of dabrafenib and trametinib. Here, we report patients treated with combination therapy after disease progression with BRAF inhibitor treatment administered before study enrollment (part B; n = 26) or after cross-over at progression with dabrafenib monotherapy (part C; n = 45). RESULTS: In parts B and C, confirmed objective response rates (ORR) were 15% (95% CI, 4% to 35%) and 13% (95% CI, 5% to 27%), respectively; an additional 50% and 44% experienced stable disease ≥ 8 weeks, respectively. In part C, median progression-free survival (PFS) was 3.6 months (95% CI, 2 to 4), and median overall survival was 11.8 months (95% CI, 8 to 25) from cross-over. Patients who previously received dabrafenib ≥ 6 months had superior outcomes with the combination compared with those treated < 6 months; median PFS was 3.9 (95% CI, 3 to 7) versus 1.8 months (95% CI, 2 to 4; hazard ratio, 0.49; P = .02), and ORR was 26% (95% CI, 10% to 48%) versus 0% (95% CI, 0% to 15%). CONCLUSION: Dabrafenib plus trametinib has modest clinical efficacy in patients with BRAF inhibitor-resistant melanoma. This regimen may be a therapeutic strategy for patients who previously benefited from BRAF inhibitor monotherapy ≥ 6 months but demonstrates minimal efficacy after rapid progression with BRAF inhibitor therapy.

15 Clinical Trial A cancer vaccine induces expansion of NY-ESO-1-specific regulatory T cells in patients with advanced melanoma. 2012

Ebert, Lisa M / MacRaild, Sarah E / Zanker, Damien / Davis, Ian D / Cebon, Jonathan / Chen, Weisan. ·Ludwig Institute for Cancer Research (Melbourne-Austin Branch), Melbourne, Australia. ·PLoS One · Pubmed #23110239.

ABSTRACT: Cancer vaccines are designed to expand tumor antigen-specific T cells with effector function. However, they may also inadvertently expand regulatory T cells (Treg), which could seriously hamper clinical efficacy. To address this possibility, we developed a novel assay to detect antigen-specific Treg based on down-regulation of surface CD3 following TCR engagement, and used this approach to screen for Treg specific to the NY-ESO-1 tumor antigen in melanoma patients treated with the NY-ESO-1/ISCOMATRIX™ cancer vaccine. All patients tested had Treg (CD25(bright) FoxP3(+) CD127(neg)) specific for at least one NY-ESO-1 epitope in the blood. Strikingly, comparison with pre-treatment samples revealed that many of these responses were induced or boosted by vaccination. The most frequently detected response was toward the HLA-DP4-restricted NY-ESO-1(157-170) epitope, which is also recognized by effector T cells. Notably, functional Treg specific for an HLA-DR-restricted epitope within the NY-ESO-1(115-132) peptide were also identified at high frequency in tumor tissue, suggesting that NY-ESO-1-specific Treg may suppress local anti-tumor immune responses. Together, our data provide compelling evidence for the ability of a cancer vaccine to expand tumor antigen-specific Treg in the setting of advanced cancer, a finding which should be given serious consideration in the design of future cancer vaccine clinical trials.

16 Clinical Trial Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. 2012

Flaherty, Keith T / Infante, Jeffery R / Daud, Adil / Gonzalez, Rene / Kefford, Richard F / Sosman, Jeffrey / Hamid, Omid / Schuchter, Lynn / Cebon, Jonathan / Ibrahim, Nageatte / Kudchadkar, Ragini / Burris, Howard A / Falchook, Gerald / Algazi, Alain / Lewis, Karl / Long, Georgina V / Puzanov, Igor / Lebowitz, Peter / Singh, Ajay / Little, Shonda / Sun, Peng / Allred, Alicia / Ouellet, Daniele / Kim, Kevin B / Patel, Kiran / Weber, Jeffrey. ·Massachusetts General Hospital Cancer Center, Boston, USA. ·N Engl J Med · Pubmed #23020132.

ABSTRACT: BACKGROUND: Resistance to therapy with BRAF kinase inhibitors is associated with reactivation of the mitogen-activated protein kinase (MAPK) pathway. To address this problem, we conducted a phase 1 and 2 trial of combined treatment with dabrafenib, a selective BRAF inhibitor, and trametinib, a selective MAPK kinase (MEK) inhibitor. METHODS: In this open-label study involving 247 patients with metastatic melanoma and BRAF V600 mutations, we evaluated the pharmacokinetic activity and safety of oral dabrafenib (75 or 150 mg twice daily) and trametinib (1, 1.5, or 2 mg daily) in 85 patients and then randomly assigned 162 patients to receive combination therapy with dabrafenib (150 mg) plus trametinib (1 or 2 mg) or dabrafenib monotherapy. The primary end points were the incidence of cutaneous squamous-cell carcinoma, survival free of melanoma progression, and response. Secondary end points were overall survival and pharmacokinetic activity. RESULTS: Dose-limiting toxic effects were infrequently observed in patients receiving combination therapy with 150 mg of dabrafenib and 2 mg of trametinib (combination 150/2). Cutaneous squamous-cell carcinoma was seen in 7% of patients receiving combination 150/2 and in 19% receiving monotherapy (P=0.09), whereas pyrexia was more common in the combination 150/2 group than in the monotherapy group (71% vs. 26%). Median progression-free survival in the combination 150/2 group was 9.4 months, as compared with 5.8 months in the monotherapy group (hazard ratio for progression or death, 0.39; 95% confidence interval, 0.25 to 0.62; P<0.001). The rate of complete or partial response with combination 150/2 therapy was 76%, as compared with 54% with monotherapy (P=0.03). CONCLUSIONS: Dabrafenib and trametinib were safely combined at full monotherapy doses. The rate of pyrexia was increased with combination therapy, whereas the rate of proliferative skin lesions was nonsignificantly reduced. Progression-free survival was significantly improved. (Funded by GlaxoSmithKline; ClinicalTrials.gov number, NCT01072175.).

17 Article Real-world efficacy and toxicity of combined nivolumab and ipilimumab in patients with metastatic melanoma. 2019

Parakh, Sagun / Randhawa, Manreet / Nguyen, Bella / Warburton, Lydia / Hussain, Mohammad Akhtar / Cebon, Jonathan / Millward, Michael / Yip, Desmond / Ali, Sayed. ·Department of Medical Oncology, Austin Health, Melbourne, Victoria, Australia. · Olivia Newton-John Cancer Research Institute, Melbourne, Victoria, Australia. · La Trobe University School of Cancer Medicine, Melbourne, Victoria, Australia. · Department of Medical Oncology, Canberra Region Cancer Centre, The Canberra Hospital, ACT, Australia. · Department of Medical Oncology, Sir Charles Gairdner Hospital, WA, Australia. · Western Australia Centre for Rural Health, University of Western Australia, WA, Australia. · School of Population and Global Health, University of Western Australia, WA, Australia. · ANU Medical School, Australian National University, ACT, Australia. ·Asia Pac J Clin Oncol · Pubmed #30426665.

ABSTRACT: BACKGROUND: There is limited real-world data on the efficacy and safety of combination programmed cell death protein-1 (PD-1) inhibitor, nivolumab and the cytotoxic T-lymphocyte antigen (CTLA-4) inhibitor ipilimumab. METHOD: We retrospectively identified patients (pts) with metastatic melanoma treated with three-weekly nivolumab (1 mg/kg) in combination with ipilimumab (3 mg/kg) for four cycles followed by nivolumab monotherapy (3 mg/kg) fortnightly. Patient demographics and treatment parameters were collected and outcomes determined. RESULTS: A total of 45 pts received combination treatment with a median follow up of 8.7 months (range 0.33-25.9 months). A total of 67% were male, and BRAF V600 mutations detected in 38%. At treatment commencement, 14 (31%) pts had brain metastases, 51% had an elevated LDH and 18 (40%) were treatment-naive. Almost a third (30%) required corticosteroids for symptom control or management of prior toxicities. Nineteen (42%) patients had prior anti-PD-1 therapy. The disease control rate (DCR) was 54% and objective response rate (ORR) was 29%. Of pts treated with prior immune checkpoint inhibitors, the DCR and ORR were 50% and 33%, respectively. Intracranial responses were observed in 18% (n = 2). The median progression-free survival (PFS) was 5.8 months (95% Confidence interval (CI), 2.9-14.1 months). PFS was higher in treatment naïve patients compared to those who had prior immunotherapy (6.2 months vs 4.9 months, P = 0.59). The median OS was 17.4 months (95% CI, 7.1-NR). pts requiring corticosteroids had a shorter PFS (4.9 months vs 6.8 months) and OS (7.1 months vs NR, P = 0.01).Treatment-related adverse events of any grade were experienced by 88% of pts, with 54% having grade 3-4 adverse events. Treatment discontinuation due to adverse events occurred in 44% of pts. CONCLUSION: In this study, responses to combination immunotherapy were lower than reported. Patients treated with prior immunotherapy had similar responses as treatment-naïve pts. The toxicity profile seen in this study is similar to those reported in clinical trials.

18 Article Rheumatic immune-related adverse events secondary to anti-programmed death-1 antibodies and preliminary analysis on the impact of corticosteroids on anti-tumour response: A case series. 2018

Mitchell, Emma L / Lau, Peter Kar Han / Khoo, Chloe / Liew, David / Leung, Jessica / Liu, Bonnia / Rischin, Adam / Frauman, Albert G / Kee, Damien / Smith, Kortnye / Brady, Benjamin / Rischin, Danny / Gibson, Andrew / Mileshkin, Linda / Klein, Oliver / Weickhardt, Andrew / Arulananda, Surein / Shackleton, Mark / McArthur, Grant / Östör, Andrew / Cebon, Jonathan / Solomon, Benjamin / Buchanan, Russell Rc / Wicks, Ian P / Lo, Serigne / Hicks, Rodney J / Sandhu, Shahneen. ·Department of Rheumatology, Royal Melbourne Hospital, Australia; Department of Rheumatology, Austin Health, Melbourne, Australia. · Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Australia. · Department of Rheumatology, Austin Health, Melbourne, Australia; Department of Clinical Pharmacology and Therapeutics, Austin Health, Melbourne, Australia; Department of Medicine, University of Melbourne, Australia. · Department of Rheumatology, Austin Health, Melbourne, Australia. · Alfred Hospital, Melbourne, Australia. · Department of Clinical Pharmacology and Therapeutics, Austin Health, Melbourne, Australia; Department of Medicine, University of Melbourne, Australia. · Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Australia; Cabrini Health, Melbourne, Australia. · Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Australia; Sir Peter MacCallum Department, University of Melbourne, Melbourne, Australia. · Cabrini Health, Melbourne, Australia. · Olivia Newton-John Cancer and Wellness Centre, Heidelberg, Victoria, Australia. · Department of Medicine, University of Melbourne, Australia; Olivia Newton-John Cancer and Wellness Centre, Heidelberg, Victoria, Australia. · Department of Rheumatology, Austin Health, Melbourne, Australia; Department of Medicine, University of Melbourne, Australia. · Department of Rheumatology, Royal Melbourne Hospital, Australia; Walter and Eliza Hall Institute, Melbourne, Australia. · Melanoma Institute Australia, University of Sydney, Sydney, New South Wales, Australia; Institute for Research and Medical Consultations, University of Dammam, Dammam, Saudi Arabia. · Sir Peter MacCallum Department, University of Melbourne, Melbourne, Australia. · Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Australia; Sir Peter MacCallum Department, University of Melbourne, Melbourne, Australia. Electronic address: shahneen.sandhu@petermac.org. ·Eur J Cancer · Pubmed #30439628.

ABSTRACT: IMPORTANCE: Rheumatic immune-related adverse events (irAEs) occur in approximately 10-20% of anti-programmed death 1 (anti-PD1)-treated cancer patients. There are limited data on the natural history, optimal treatment and long-term oncological outcomes of patients with rheumatic irAEs. OBJECTIVE: The objective of the study was to describe the spectrum and natural history of rheumatic irAEs and the potential impact of rheumatic irAEs and immunomodulators on anti-PD1 tumour efficacy. METHODS: Cancer patients with pre-existing rheumatic disease before anti-PD1 therapy or de novo rheumatic irAEs on anti-PD1 therapy were retrospectively reviewed across three sites. Patient demographics, treatment history, anti-PD1 irAEs, and anti-PD1 responses were evaluated. Relationships between the development or pre-existence of rheumatic irAE, use of immunomodulatory agents and outcomes were evaluated. RESULTS: This multicenter case series describes 36 cancer patients who had rheumatic disease before anti-PD1 therapy (n = 12) or developed de novo rheumatic irAEs (n = 24). Thirty-four of the 36 patients sustained rheumatic irAEs (median time to rheumatic irAE: 14.5 weeks), including 24 de novo (18 inflammatory arthritis, three myositis, two polymyalgia rheumatica, one fasciitis) and 10 flares in 12 patients with pre-existing rheumatic disease. Corticosteroids were used in 30 of 36 patients (median duration: 10 months), and disease-modifying antirheumatic drugs were used in 14 of 36 patients (median duration: 5.5 months). The objective response rate to anti-PD1 therapy was 69% (n = 25/36) overall and 81% (n = 21/26) in the melanoma subgroup. CONCLUSIONS: Rheumatic irAEs are often chronic and require prolonged immunomodulatory therapy. Prospective studies are required to define optimal management of rheumatic irAEs that maintain long-term anticancer outcomes.

19 Article Neutrophil to lymphocyte ratio is an independent predictor of outcome for patients undergoing definitive resection for stage IV melanoma. 2018

Kanatsios, Stefanos / Melanoma Project, Melbourne / Li Wai Suen, Connie S N / Cebon, Jonathan Simon / Gyorki, David E. ·Austin Health, Heidelberg, VIC, Australia. · Olivia Newton-John Cancer Research Institute, La Trobe University School of Cancer Medicine, Heidelberg, VIC, Australia. · University of Melbourne, Parkville, VIC, Australia. · Division of Cancer Surgery, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. ·J Surg Oncol · Pubmed #30196539.

ABSTRACT: BACKGROUND AND OBJECTIVES: The aim of this study was to perform a retrospective analysis of survival rates and determine prognostic indicators for patients who underwent definitive surgical resection of stage IV melanoma. METHODS: Patients included were those who underwent complete resection of metastatic melanoma. Data was analyzed using IBM SPSS 2.0. Survival estimates were derived from Kaplan-Meier, log-rank, and Breslow tests. RESULTS: The study population (n = 95) consisted of 60 males and 35 females. Median overall survival (OS) from the first metastasectomy was 49 months (95% confidence interval, 31-67 months). OS at 1, 2, and 5 years was 92%, 87%, and 50% respectively. Predictors of survival included clear surgical margins compared to patients with positive margins (median OS 53 vs 20 months, P = .026). A preoperative neutrophil to lymphocyte ratio less than 5 experienced a median OS of 65 months compared to 15 months ( P = .006; multivariable analysis for OS: hazard ratio 3.590, P = .009). CONCLUSION: This study's results are consistent with previous findings demonstrating favourable long-term outcomes following selective resection of metastatic melanoma. In addition to achieving clear surgical margins, a low preoperative neutrophil to lymphocyte ratio was associated with improved outcomes. These factors may help identify surgical candidates.

20 Article Delayed Autoimmune Toxicity Occurring Several Months After Cessation of Anti-PD-1 Therapy. 2018

Parakh, Sagun / Cebon, Jonathan / Klein, Oliver. ·Medical Oncology Unit, Austin Health, Melbourne, Victoria, Australia. · Olivia Newton-John Cancer Research Institute, Melbourne, Victoria, Australia. · La Trobe University School of Cancer Medicine, Melbourne, Victoria, Australia. · Medical Oncology Unit, Austin Health, Melbourne, Victoria, Australia oliver.klein@onjcri.org.au. ·Oncologist · Pubmed #29666298.

ABSTRACT: Treatment with anti-programmed cell death protein 1 (PD-1) antibodies has demonstrated clinical efficacy in a whole range of malignancies including advanced melanoma, renal cell cancer, bladder cancer, and non-small cell lung cancer. Immune-related adverse events are a unique side effect of checkpoint regulator therapy including anti-PD-1 antibodies. Treatment-related autoimmunity can occur in any organ system, with the median onset usually within 5-15 weeks from the commencement of therapy, depending on the organ system involved. This study describes for the first time a case of delayed autoimmunity occurring 8 months after discontinuing treatment with the anti-PD-1 antibody nivolumab in a patient with metastatic melanoma. The case highlights the need for ongoing surveillance of patients treated with immune checkpoint inhibitors even after cessation of therapy, especially as patients increasingly stop treatment after achieving durable responses.

21 Article Characterising the phenotypic evolution of circulating tumour cells during treatment. 2018

Tsao, Simon Chang-Hao / Wang, Jing / Wang, Yuling / Behren, Andreas / Cebon, Jonathan / Trau, Matt. ·Centre for Personalised Nanomedicine, Australian Institute for Bioengineering and Nanotechnology, University of Queensland, Brisbane, QLD, 4072, Australia. · Olivia Newton-John Cancer Research Institute, Heidelberg, VIC, 3084, Australia. · Department of Surgery, University of Melbourne, Austin Health, Heidelberg, VIC, 3084, Australia. · Centre for Personalised Nanomedicine, Australian Institute for Bioengineering and Nanotechnology, University of Queensland, Brisbane, QLD, 4072, Australia. yuling.wang@mq.edu.au. · Department of Molecular Sciences, Faculty of Science and Engineering, Macquarie University, Sydney, 2109, Australia. yuling.wang@mq.edu.au. · School of Cancer Medicine, La Trobe University, Bundoora, VIC, 3086, Australia. · Centre for Personalised Nanomedicine, Australian Institute for Bioengineering and Nanotechnology, University of Queensland, Brisbane, QLD, 4072, Australia. m.trau@uq.edu.au. · School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, QLD, 4072, Australia. m.trau@uq.edu.au. ·Nat Commun · Pubmed #29662054.

ABSTRACT: Real-time monitoring of cancer cells' phenotypic evolution during therapy can provide vital tumour biology information for treatment management. Circulating tumour cell (CTC) analysis has emerged as a useful monitoring tool, but its routine usage is restricted by either limited multiplexing capability or sensitivity. Here, we demonstrate the use of antibody-conjugated and Raman reporter-coated gold nanoparticles for simultaneous labelling and monitoring of multiple CTC surface markers (named as "cell signature"), without the need for isolating individual CTCs. We observe cell heterogeneity and phenotypic changes of melanoma cell lines during molecular targeted treatment. Furthermore, we follow the CTC signature changes of 10 stage-IV melanoma patients receiving immunological or molecular targeted therapies. Our technique maps the phenotypic evolution of patient CTCs sensitively and rapidly, and shows drug-resistant clones having different CTC signatures of potential clinical value. We believe our proposed method is of general interest in the CTC relevant research and translation fields.

22 Article Intercellular Resistance to BRAF Inhibition Can Be Mediated by Extracellular Vesicle-Associated PDGFRβ. 2017

Vella, Laura J / Behren, Andreas / Coleman, Bradley / Greening, David W / Hill, Andrew F / Cebon, Jonathan. ·Olivia Newton-John Cancer Research Institute, Level 5 Olivia Newton-John Cancer and Wellness Centre, Austin Health, Studley Road, Heidelberg, VIC 3084, Australia; The Florey Institute for Neuroscience and Mental Health, 30 Royal Parade, Parkville, VIC 3052, Australia. Electronic address: ljvella@unimelb.edu.au. · Olivia Newton-John Cancer Research Institute, Level 5 Olivia Newton-John Cancer and Wellness Centre, Austin Health, Studley Road, Heidelberg, VIC 3084, Australia; School of Cancer Medicine, La Trobe University, Heidelberg, VIC 3084, Heidelberg. · Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Bundoora, VIC 3083, Australia. ·Neoplasia · Pubmed #28963969.

ABSTRACT: Treatment of BRAF mutant melanoma with kinase inhibitors has been associated with rapid tumor regression; however, this clinical benefit is short-lived, and most patients relapse. A number of studies suggest that the extracellular environment promotes BRAF inhibitor resistance and tumor progression. Extracellular vesicles, such as exosomes, are functional mediators in the extracellular environment. They are small vesicles known to carry a concentrated group of functional cargo and serve as intercellular communicators not only locally but also systemically. Increasingly, it is reported that extracellular vesicles facilitate the development of drug resistance in cancer; however, their role in BRAF inhibitor resistance in melanoma is unclear. Here we investigated if extracellular vesicles from BRAF inhibitor-resistant melanoma could influence drug sensitivity in recipient melanoma cells. We demonstrate that the resistance driver, PDGFRβ, can be transferred to recipient melanoma cells via extracellular vesicles, resulting in a dose-dependent activation of PI3K/AKT signaling and escape from MAPK pathway BRAF inhibition. These data suggest that the BRAF inhibitor-sensitive phenotype of metastatic melanoma can be altered by delivery of PDGFRβ by extracellular vesicles derived from neighboring drug-resistant melanoma cells.

23 Article Pooled Analysis Safety Profile of Nivolumab and Ipilimumab Combination Therapy in Patients With Advanced Melanoma. 2017

Sznol, Mario / Ferrucci, Pier Francesco / Hogg, David / Atkins, Michael B / Wolter, Pascal / Guidoboni, Massimo / Lebbé, Celeste / Kirkwood, John M / Schachter, Jacob / Daniels, Gregory A / Hassel, Jessica / Cebon, Jonathan / Gerritsen, Winald / Atkinson, Victoria / Thomas, Luc / McCaffrey, John / Power, Derek / Walker, Dana / Bhore, Rafia / Jiang, Joel / Hodi, F Stephen / Wolchok, Jedd D. ·Mario Sznol, Yale Comprehensive Cancer Center, New Haven, CT · Pier Francesco Ferrucci, Istituto Europeo di Oncologia, Milan · Massimo Guidoboni, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori, Meldola, Italy · David Hogg, Princess Margaret Cancer Centre, Toronto, Ontario, Canada · Michael B. Atkins, Georgetown-Lombardi Comprehensive Cancer Center, Washington, DC · Pascal Wolter, University Hospitals Leuven, Leuven, Belgium · Celeste Lebbé, Université Paris Diderot, Paris · Luc Thomas, Centre Hospitalier Lyon-Sud, Pierre-Bénite, France · John M. Kirkwood, Hillman Cancer Center, Pittsburgh, PA · Jacob Schachter, Sheba Medical Center, Ramat Gan, Israel · Gregory A. Daniels, University of California San Diego, Moores Cancer Center, La Jolla, CA · Jessica Hassel, University Hospital, Heidelberg, Germany · Jonathan Cebon, Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria · Winald Gerritsen, University of Queensland, St Lucia · Victoria Atkinson, Gallipoli Medical Research Foundation, Greenslopes · Victoria Atkinson, Princess Alexandra Hospital, Brisbane, Queensland, Australia · Winald Gerritsen, Radboud University Medical Center, Nijmegen, the Netherlands · John McCaffrey, Irish Clinical Oncology Research Group, Dublin · Derek Power, Irish Clinical Oncology Research Group, Cork, Ireland · Dana Walker, Rafia Bhore, and Joel Jiang, Bristol-Myers Squibb, Princeton, NJ · F. Stephen Hodi, Dana-Farber Cancer Institute, Boston, MA · and Jedd D. Wolchok, Parker Institute and Ludwig Center at Memorial Sloan Kettering Cancer Center, New York, NY. ·J Clin Oncol · Pubmed #28915085.

ABSTRACT: Purpose The addition of nivolumab (anti-programmed death-1 antibody) to ipilimumab (anti-cytotoxic T-cell lymphocyte-associated 4 antibody) in patients with advanced melanoma improves antitumor response and progression-free survival but with a higher frequency of adverse events (AEs). This cross-melanoma study describes the safety profile of the approved nivolumab plus ipilimumab regimen. Methods This retrospective safety review on data from three trials (phase I, II, and III) included patients with advanced melanoma who received at least one dose of nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks × 4 and then nivolumab 3 mg/kg every 2 weeks until disease progression or unacceptable toxicity while following established guidelines for AE management. Analyses were of all treatment-related AEs, select (immune-related) AEs, time to onset and resolution, and use of immune-modulating agents and their effects on outcome. Results Among 448 patients, median duration of follow-up was 13.2 months. Treatment-related grade 3/4 AEs occurred in 55.5% of patients; 35.7% had treatment-related AEs that led to discontinuation. The most frequent treatment-related select AEs of any grade were skin (64.3%) and GI (46.7%) and of grade 3/4, hepatic (17.0%) and GI (16.3%); 30.1% developed a grade 2 to 4 select AE in more than one organ category. Median time to onset of grade 3/4 treatment-related select AEs ranged from 3.1 (skin) to 16.3 (renal) weeks, and with the exclusion of endocrine AEs, median time to resolution from onset ranged from 1.9 (renal) to 4.5 (pulmonary) weeks, with resolution rates between 79% and 100% while using immune-modulating agents. Four (< 1%) on-study deaths were attributed to therapy. Conclusion Frequency of grade 3/4 treatment-related AEs was higher with nivolumab plus ipilimumab and occurred earlier than historical experience with either agent alone, but resolution rates were similar.

24 Article Efficacy of anti-PD-1 therapy in patients with melanoma brain metastases. 2017

Parakh, Sagun / Park, John J / Mendis, Shehara / Rai, Rajat / Xu, Wen / Lo, Serigne / Drummond, Martin / Rowe, Catherine / Wong, Annie / McArthur, Grant / Haydon, Andrew / Andrews, Miles C / Cebon, Jonathan / Guminski, Alex / Kefford, Richard F / Long, Georgina V / Menzies, Alexander M / Klein, Oliver / Carlino, Matteo S. ·Medical Oncology Unit, Austin Health, Melbourne, Victoria 3084, Australia. · Olivia Newton-John Cancer Research Institute, Melbourne, Victoria 3084, Australia. · La Trobe University School of Cancer Medicine, Melbourne, Victoria 3086, Australia. · Crown Princess Mary Cancer Centre, Westmead Hospital, Sydney, New South Wales 2145, Australia. · The University of Sydney, Sydney, New South Wales 2006, Australia. · Medical Oncology Unit, Alfred Hospital, Melbourne, Victoria 3004, Australia. · Melanoma Institute Australia, Sydney, New South Wales 2060, Australia. · Peter MacCallum Cancer Centre, Melbourne, Victoria 3000, Australia. · Royal North Shore and Mater Hospitals, Sydney, New South Wales 2065, Australia. · Department of Clinical Medicine, Macquarie University, New South Wales 2109, Australia. ·Br J Cancer · Pubmed #28524161.

ABSTRACT: BACKGROUND: There is limited data on the efficacy of anti-programmed death 1 (PD-1) antibodies in patients (pts) with melanoma brain metastasis (BM), particularly those which are symptomatic. METHOD: We retrospectively assessed pts with melanoma BM treated with PD-1 antibodies, nivolumab and pembrolizumab. Clinicopathologic and treatment parameters were collected and outcomes determined for intracranial (IC) response rate (RR) using a modified RECIST criteria, with up to five IC target lesions used to determine IC response, disease control rate (DCR) and progression-free survival (PFS). RESULTS: A total of 66 pts were identified with a median follow up of 7.0 months (range 0.8-24.5 months). A total of 68% were male and 45% BRAF V600 mutation positive. At PD-1 antibody commencement, 50% had an elevated LDH; 64% had local therapy to BM prior to commencing anti-PD1, of which 5% had surgical resection, 14% stereotactic radiosurgery (SRS), 18% whole-brain radiotherapy (WBRT), 27% had surgery and radiotherapy. Twenty-one per cent started anti-PD-1 as first line systemic therapy. No pt had prior anti-PD-1 treatment. The IC overall RR was 21 and DCR 56%. Responses occurred in 21% of pts with symptomatic BM. The median OS was 9.9 months (95% CI 6.93-17.74). Pts with symptomatic BM had shorter PFS than those without symptoms (2.7 vs 7.4 months, P=0.035) and numerically shorter OS (5.7 vs 13.0 months, P=0.068). Pts requiring corticosteroids also had a numerically shorter PFS (3.2 vs 7.4 months, P=0.081) and OS (4.8 vs 13.1 months, P=0.039). CONCLUSIONS: IC responses to anti-PD-1 antibodies occur in pts with BM, including those with symptomatic BM requiring corticosteroids. Prospective trials evaluating anti-PD-1 therapy in pts with BM are underway.

25 Article Whole-genome landscapes of major melanoma subtypes. 2017

Hayward, Nicholas K / Wilmott, James S / Waddell, Nicola / Johansson, Peter A / Field, Matthew A / Nones, Katia / Patch, Ann-Marie / Kakavand, Hojabr / Alexandrov, Ludmil B / Burke, Hazel / Jakrot, Valerie / Kazakoff, Stephen / Holmes, Oliver / Leonard, Conrad / Sabarinathan, Radhakrishnan / Mularoni, Loris / Wood, Scott / Xu, Qinying / Waddell, Nick / Tembe, Varsha / Pupo, Gulietta M / De Paoli-Iseppi, Ricardo / Vilain, Ricardo E / Shang, Ping / Lau, Loretta M S / Dagg, Rebecca A / Schramm, Sarah-Jane / Pritchard, Antonia / Dutton-Regester, Ken / Newell, Felicity / Fitzgerald, Anna / Shang, Catherine A / Grimmond, Sean M / Pickett, Hilda A / Yang, Jean Y / Stretch, Jonathan R / Behren, Andreas / Kefford, Richard F / Hersey, Peter / Long, Georgina V / Cebon, Jonathan / Shackleton, Mark / Spillane, Andrew J / Saw, Robyn P M / López-Bigas, Núria / Pearson, John V / Thompson, John F / Scolyer, Richard A / Mann, Graham J. ·Melanoma Institute Australia, The University of Sydney, North Sydney, Sydney, New South Wales 2065, Australia. · QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4006, Australia. · Discipline of Pathology, Sydney Medical School, The University of Sydney, Sydney, New South Wales 2006, Australia. · Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland 4072, Australia. · Australian Institute of Tropical Health and Medicine, James Cook University, Cairns, Queensland 4878, Australia. · Los Alamos National Laboratory, Los Alamos, New Mexico 87545, USA. · Research Program on Biomedical Informatics, IMIM Hospital del Mar Medical Research Institute, Universitat Pompeu Fabra, 08003 Barcelona, Catalonia, Spain. · Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, 08028 Barcelona, Spain. · Centre for Cancer Research, Westmead Institute for Medical Research, The University of Sydney, Westmead, Sydney, New South Wales 2145, Australia. · Children's Medical Research Institute, The University of Sydney, Westmead, Sydney, New South Wales 2145, Australia. · Children's Hospital at Westmead, The University of Sydney, Westmead, New South Wales Sydney, 2145, Australia. · Bioplatforms Australia, North Ryde, Sydney, New South Wales 2109, Australia. · University of Melbourne Centre for Cancer Research, University of Melbourne, Parkville, Melbourne, Victoria 3052, Australia. · School of Mathematics and Statistics, The University of Sydney, Sydney, New South Wales 2006, Australia. · Olivia Newton-John Cancer Research Institute, La Trobe University, Austin Health, Heidelberg, Melbourne, Victoria 3084, Australia. · Macquarie University, North Ryde, Sydney, New South Wales 2109, Australia. · Centenary Institute, The University of Sydney, Sydney, New South Wales 2006, Australia. · Department of Medical Oncology, Royal North Shore Hospital, St Leonards, Sydney, New South Wales 2065, Australia. · Peter MacCallum Cancer Centre and University of Melbourne, Melbourne, Victoria 3000, Australia. · Institució Catalana de Recerca i Estudis Avançats (ICREA), 08010 Barcelona, Spain. · Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Camperdown, Sydney, New South Wales 2050, Australia. ·Nature · Pubmed #28467829.

ABSTRACT: Melanoma of the skin is a common cancer only in Europeans, whereas it arises in internal body surfaces (mucosal sites) and on the hands and feet (acral sites) in people throughout the world. Here we report analysis of whole-genome sequences from cutaneous, acral and mucosal subtypes of melanoma. The heavily mutated landscape of coding and non-coding mutations in cutaneous melanoma resolved novel signatures of mutagenesis attributable to ultraviolet radiation. However, acral and mucosal melanomas were dominated by structural changes and mutation signatures of unknown aetiology, not previously identified in melanoma. The number of genes affected by recurrent mutations disrupting non-coding sequences was similar to that affected by recurrent mutations to coding sequences. Significantly mutated genes included BRAF, CDKN2A, NRAS and TP53 in cutaneous melanoma, BRAF, NRAS and NF1 in acral melanoma and SF3B1 in mucosal melanoma. Mutations affecting the TERT promoter were the most frequent of all; however, neither they nor ATRX mutations, which correlate with alternative telomere lengthening, were associated with greater telomere length. Most melanomas had potentially actionable mutations, most in components of the mitogen-activated protein kinase and phosphoinositol kinase pathways. The whole-genome mutation landscape of melanoma reveals diverse carcinogenic processes across its subtypes, some unrelated to sun exposure, and extends potential involvement of the non-coding genome in its pathogenesis.

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